Switching from ultrafast electron transfer to proton transfer in excited drug-protein complexes upon biotransformation
| العنوان: | Switching from ultrafast electron transfer to proton transfer in excited drug-protein complexes upon biotransformation |
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| المؤلفون: | Lorena Tamarit, Meryem El Ouardi, Emilio Lence, Inmaculada Andreu, Concepción González-Bello, Ignacio Vayá, Miguel A. Miranda |
| المساهمون: | Ministerio de Ciencia e Innovación (España) |
| المصدر: | CHEMICAL SCIENCE r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe instname |
| بيانات النشر: | Royal Society of Chemistry (UK), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | BINDING, RECEPTOR-TYROSINE KINASE, INHIBITOR, ALBUMIN, ATOM, General Chemistry, PLASMA-PROTEINS, CANCER, GEFITINIB, TRYPTOPHAN |
| الوصف: | Photosensitization by drugs is directly related with the excited species and the photoinduced processes arising from interaction with UVA light. In this context, the ability of gefitinib (GFT), a tyrosine kinase inhibitor (TKI) used for the treatment of a variety of cancers, to induce phototoxicity and photooxidation of proteins has recently been demonstrated. In principle, photodamage can be generated not only by a given drug but also by its photoactive metabolites that maintain the relevant chromophore. In the present work, a complete study of O-desmorpholinopropyl gefitinib (GFT-MB) has been performed by means of fluorescence and ultrafast transient absorption spectroscopies, in addition to molecular dynamics (MD) simulations. The photobehavior of the GFT-MB metabolite in solution is similar to that of GFT. However, when the drug or its metabolite are in a constrained environment, i.e. within a protein, their behavior and the photoinduced processes that arise from their interaction with UVA light are completely different. For GFT in complex with human serum albumin (HSA), locally excited (LE) singlet states are mainly formed; these species undergo photoinduced electron transfer with Tyr and Trp. By contrast, since GFT-MB is a phenol, excited state proton transfer (ESPT) to form phenolate-like excited species might become an alternative deactivation pathway. As a matter of fact, the protein-bound metabolite exhibits higher fluorescence yields and longer emission wavelengths and lifetimes than GFT@HSA. Ultrafast transient absorption measurements support direct ESPT deprotonation of LE states (rather than ICT), to form phenolate-like species. This is explained by MD simulations, which reveal a close interaction between the phenolic OH group of GFT-MB and Val116 within site 3 (subdomain IB) of HSA. The reported findings are relevant to understand the photosensitizing properties of TKIs and the role of biotransformation in this type of adverse side effects. Financial support from the Spanish Ministry of Science and Innovation (RYC-2015-17737, BEAGAL 18/00211, PID2020-115010RB-I00/AEI/10.13039/501100011033, FPU19/00048, PID2019-105512RB-I00/AEI/10.13039/501100011033), the Xunta de Galicia (ED431C 2021/29), the Centro singular de investigación de Galicia accreditation 2019–2022 (ED431G 2019/03), and the European Regional Development Fund (ERDF) is gratefully acknowledged. All authors are grateful to the Centro de Supercomputación de Galicia (CESGA) for use of the Finis Terrae computer. |
| تدمد: | 2041-6539 2041-6520 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7a1fa12da151fe672c24ca40d77d61b4 http://hdl.handle.net/10261/303992 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....7a1fa12da151fe672c24ca40d77d61b4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20416539 20416520 |
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